Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/ KsJ-Lepr db/db mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85 , or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0·05) in both tissues from db/db mice. Insulin increased Akt-Ser 473 phosphorylation by two-to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser 473 phosphorylation was decreased by 32% (P<0·05) and 69% (P<0·05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0·05). The level of insulin-stimulated tyrosine phosphorylation of p85 from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0·05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.

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The recently cloned obesity gene (ob) encodes a protein, leptin, which is secreted from adipose tissue and interacts with hypothalamic receptors to decrease appetite, increase energy expenditure, and reduce body lipid stores. The levels of ob mRNA are increased in several models of obesity, consistent with the hypothesis that obese animals may be resistant to the actions of leptin. The present study examined the impact of increased energy expenditure through exercise training on ob mRNA gene expression and body composition in the SHHF/Mc-fa(cp) male rat, a rodent model of obesity, insulin resistance, and type II diabetes. Six week old lean and obese animals were trained 8-12 weeks by treadmill running at 70% peak oxygen uptake, 5 days/wk, for 1.5 hr/day. After endurance training, exercised rats had significantly lower total body fat compared to sedentary rats of the same age, despite maintaining the same body weight. In the obese SHHF/Mcc-fa(cp) rat, the level of ob mRNA expression was markedly increased by four fold in subcutaneous adipose tissue compared to lean controls (p<0.05). In response to exercise training, there was a significant 85 % decrease in ob mRNA in exercised-training lean rats (p < 0.05) compared with non-exercised controls, while in obese-exercised rats, ob gene expression was significantly reduced only by 50% relative to non-exercised obese rats (p < 0.05). These results demonstrate that exercise training reduces fat mass and ob mRNA in lean and obese rats, and supports the hypothesis of a feedback loop between the adipocyte and hypothalamus that attempts to maintain body weight at a constant level by reducing ob gene expression in response to increased energy expenditure.

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